NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test

Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.